REPs of DLCs in human, rat, mouse and guinea pig CALUX cell lines
the model membership probabilities with a set confidence level of 0.95 (Table S3). Among the tested congeners TCDF, 1234678-HpCDD and PCB169 and among the nontested ones, Octachlorodibenzo-p-dioxin (OCDD) and Octachlorodibenzofuran (OCDF) were considered to be moderate outliers in all models. Even though PCB126 was not an outlier based on the membership probability test, the congener showed large distance to the models in Y space. This means that the chemistry of the compound falls within the applicability domain but its response is outlying. The residuals obtained for PCB126 were more than two times higher than the standard deviation for residuals in the guinea pig and human models, and three times higher than the standard deviation for residuals in the rat and mouse models. This deviation can most likely be explained by the fact that REPs for PCB126 are more similar to those of PCDD/Fs compared to other PCBs, whereas its structure and chemistry is more similar to PCBs. QSAR models predict the potency of a congener based on chemical properties and their effect in an assay. As a consequence, developed QSAR models in this study tend to predict a considerably lower REP for PCB126, as has been determined based on the CALUX assays (Table 2, Figure 4).
b)
1
A.
0
1
PCB126
-5
-6
PCB156
0
Exp. log REP
-1 -2 -3 -4 -5 -6 -7
-1
PCB77
-7
-5
-4
-3
-2
-1
0
PCB156
PCB118
PCB153
-7
1
-4
-3
-2
12378-PeCDD 234678-HxCDF
TCDF
0
1
123478-HxCDF
0
123478-HxCDF 1234789-HpCDF 1234678-HpCDD 1234678-HpCDF
TCDD
123478-HxCDF 1234678-HpCDD 23478-PeCDF 123678-HxCDD TCDF 234678-HxCDF
-1
PCB105
-1
12378-PeCDD
PCB156 PCB189
-5
Human
PCB77
PCB189
-6
D.
23478-PeCDF PCB126
PCB74
PCB105
Pred. log REP
Guinea Pig
1234678-HpCDF
-2
PCB126
-3
PCB118
PCB167 PCB74
-7
1
Pred. log REP
-7
-4
PCB167
C.
-3
PCB189
-6
1234678-HpCDF
PCB77
-6
PCB126
23478-PeCDF TCDF 123478-HxCDF
124789-HpCDF
-2
-5
PCB118
1234678-HpCDD
PCB74
PCB153
1
PCB105
PCB167
123678-HxCDD 123478-HxCDF 234678-HxCDF TCDF 1234789-HpCDF 1234678-HpCDD 1234678-HpCDF
Exp. log REP
-4
-7
23478-PeCDF
-3
12378-PeCDD 234678-HxCDF
0
TCDD
Exp. log REP
Exp. log REP
-1 -2
B.
Mouse 12378-PeCDD
-4
PCB153
-6
-5
-4
-3
Pred. log REP
-2
-1
0
-5
1
PCB 153 PCB167 PCB74 PCB18 PCB118 PCB105 PCB169 PCB156
-5
PCB77
-4
-3
-2
Pred. log REP
-1
0
1
Figure 4. The plots of QSAR-predicted (pred) log relative effect potency (REP) values against experimental (exp) log REP values for (A) rat H4L1.1c4, (B) mouse H1L6.1c2, (C) guinea pig G16L1.1c8, and (D) human AZ-AhR cells. The blue triangles refer to the training set compounds and red circles to the validation set compounds.
153
6